Prostanoids are ubiquitous lipid mediator biomolecules involved in numerous physiological processes, such as the contraction and relaxation of smooth muscle, vasodilation, vasoconstriction, pain, regulation of blood pressure, and modulation of inflammation. Prostanoids are a family of eicosanoids that comprise prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (Txs). Their receptors belong to the G-protein coupled receptor (GPCR) superfamily of receptors and may be grouped into five classes, namely, prostaglandin D (DP), prostaglandin E (EP), prostaglandin F (FP), prostaglandin I (IP), and Thromboxane A (TP) based on their sensitivity to five naturally occurring prostanoids, PGD2, PGE2, PGF2α, PGI2, and TxA2, respectively (Coleman, R. A., Prostanoid Receptors. IUPHAR Compendium of Receptor Characterization and Classification, 2nd Edition, 338-353, 2000). EP receptors have been characterized into four subtypes EP1, EP2, EP3, and EP4. Each subtype has been cloned and is distinct at both a molecular and pharmacological level.
Prostanoids are synthesized from essential fatty acids comprising twenty carbon atoms, such as arachidonic acid and 8,11,14-eicosatrienoic acid. Prostanoids are synthesized in response to both extracellular and intracellular stimuli and are then rapidly released from the cells. In general, the short half-lives of most prostanoids ensure they act near the sites of their biosynthesis.
Prostaglandin E2 (PGE2) is a potent endogenous EP receptor agonist derived from arachidonic acid and possesses two carbon-carbon double bonds, one in each the α-chain and ω-chain, and is thus called a “Series 2” prostaglandin.
Prostaglandin E1 (PGE1) is derived from 8,11,14-eicosatrienoic acid and possesses only one carbon-carbon double bond, located in the co-chain, and is thus called a “Series 1” prostaglandin.
Both prostanoid and non-prostanoid EP receptor agonists are known. EP receptor agonists may have a number of utilities. These include, but are not limited to treatment of influenza (WO 2008/058766), bone fracture healing (Li, M., et al., J. Bone Miner. Res., 18(11), 2003, 2033-2042; Paralkar, V. M., PNAS, 100(11), 2003, 6736-6740; WO 2002/24647; WO 1998/27976), bone disease (WO 2002/24647), glaucoma (WO 2008/015517; WO 2007/027468; WO 2003/040126), ocular hypertension (WO 2003/040126), dysmenorrhoea (WO 2003/037433), pre-term labor (GB 2 293 101), immune disorders (WO 2003/037433), osteoporosis (WO 1998/27976; WO 2001/46140), asthma (WO 2003/037433), allergy (WO 2003/037433), fertility (Breyer, R. M., et al., Ann. N.Y. Acad. Sci., 905, 2000, 221-231), male sexual dysfunction (WO 2000/40248), female sexual dysfunction (U.S. Pat. No. 6,562,868), periodontal disease (WO 2000/31084), gastric ulcer (U.S. Pat. No. 5,576,347), and renal disease (WO 1998/34916). EP receptor agonists may also be useful for expansion of hematopoietic stem cell populations (WO 2008/073748; North, T. E., et al., Nature, 447, 2007, 1007-1011).